Project Summary Vision disorders in early childhood, such as strabismus, amblyopia and high hyperopia, can significantly impair the development of visual, motor, and cognitive functions. There is a need for better understanding of their disease etiology which remains mostly unknown and methods for early identification of these disorders, which still remain undetected in many children until their older ages when response to treatment is worse. Maternal smoking during pregnancy (MSP), especially sustained smoking that persisted into third trimester, has been consistently associated with several pediatric vision disorders including hyperopia, strabismus, and bilateral amblyopia, and nicotine is considered as a key chemical responsible for the effects. The broad impact of MSP on multiple vision disorders indicates that disturbance of intrauterine environment and fetal development may play an important role in the development of vision disorders that occur very early in life. However, intrauterine exposure to tobacco smoke or nicotine are not well captured by self-reported MSP, due to under-reporting, exposure to overlooked sources of smoke or nicotine (e.g., environmental tobacco smoke, nicotine replacement therapy), and variation in the uptake and metabolism of tobacco smoke by the mother and in the fetal response to intrauterine disturbance. Objective and reliable measures of biologically effective dose of intrauterine exposure to tobacco smoke or early biological effects of this exposure are needed. There have been major advances in identifying specific genomic loci that are differentially methylated in newborns in response to MSP and accumulating evidence linking alterations to DNA methylation at birth with childhood diseases and outcomes such as low birth weight. These led us to hypothesize that epigenetic changes can alter the development of the vision system in the fetus, leading to the development of vision disorders in early childhood. To test this hypothesis, we propose to conduct a case-control study nested within the Multiethnic Pediatric Eye Disease Study (MEPEDS) and retrieve neonatal dried blood spots (DBSs) that had been collected by the California State?s Genetic Disease Screening Program from MEPEDS children at their birth. Using these biospecimens, we will 1) assess the relationship of cotinine level in DBS and tobacco dosimeter based on DNA methylation marks, in comparison to self-reported MSP, with strabismus, bilateral decreased visual acuity, and hyperopia in 1508 preschool children; and 2) investigate epigenetic susceptibility loci for hyperopia by comparing DNA methylation in neonatal DBS from 508 cases and an equal number of random controls. Findings from this proposed study will have a great impact on assessing population and individual risks from intrauterine exposure to different sources of tobacco smoke, understanding underlying biological mechanisms, early screening of pediatric vision disorders, and preventing adverse impacts of these vision disorders.